Malignant tumor is one of the most severe diseases threatening the human physical health, and has become the second leading cause of death, right behind the cardiovascular disease.
Moreover, the most recent statistical data indicate that the incidence rate and the death rate of malignant tumor are rising up year by year all over the world, especially in the developing countries.
The chemotherapy is the most important treatment means for malignant tumor besides operation and radiotherapy. The traditional chemotherapeutics mainly act on DNA, RNA, microtubule protein and the like, which are the common parts involving the life and death of all cells, and therefore have low selectivity and high toxicity. The targeted medicines act on the key molecules in the tumor cell, which regulate the cell growth and proliferation and are quite different from the normal cell, and their signal transduction pathways. They have the advantages such as a high selectivity on the tumor cells and low toxicity to normal tissues, and therefore become a hot point in the study of anti-tumor drug.
In many of molecules regulating signal transduction pathway of the cell, the family of protein kinases is the most important signal transduction molecule. It is found in the study that the occurrence and development of many tumors are relevant to the gene abnormality or excess activation of protein kinase. Therefore, protein kinases have become the most important anti-tumor treatment target. Tyrosine or serine/threonine protein kinase such as EGFR (Epidermal Growth Factor Receptor), VEGFR (Vascular Endothelial Growth Factor Receptor), PDGFR (Platelet Derived Growth Factor Receptor), c-Kit, c-SRC, MET, BTK, ALK, Abl, and FLT3 are most important among the members of the family of protein kinases, and have been listed as oncogene or oncoprotein.
Currently, more than 10 small molecule inhibitors targeting these tyrosine and serine/threonine protein kinases have been applied to clinical tumor treatment. The typical example includes: two EGFR inhibitors, i.e., Gefitinib and Erlotinib, mainly useful for the treatment of non-small cell lung carcinoma; two new-vessel inhibitors (their main targets are VEGFR, PDGFR and the like), i.e., Sunitinib and Sorafenib, useful for the anti-new-vessels treatment in the solid tumor; and Bcr-Abl kinase inhibitor Imatinib, mainly useful for the treatment of chronic myelocytic leukemia with positive Philadelphia chromosome.
However, these current antitumor drugs target a single or a very small number of kinase oncogenes or oncoproteins and therefore have the disadvantages such as low efficiency and being prone to develop the drug resistance. The typical example includes EGFR kinase inhibitors Gefitinib and Erlotinib. These two drugs have good effects on only 10-20% of patients with non-small cell lung carcinoma. It is found in the study on its mechanism of action that Gefitinib and Erlotinib belong to the selective EGFR kinase inhibitor, and are most sensitive to the patients having deletion mutation of exon 19 or L858R point mutation of exon 21 in EGFR (deletion mutation of exon 19 and L858R point mutation of exon 21 in EGFR are collectively referred to as EGFR sensitive mutation). Even if these patients with EGFR sensitive mutation are treated with Gefitinib and Erlotinib, most of them have developed the drug resistance after 6-9 months. It is found that there are many reasons for the development of the drug resistance, which mainly include (1) a second mutation occurs based on EGFR sensitive mutation, i.e., T790M mutation in EGFR; and (2) MET gene (MET is a tyrosine kinase) is subjected to amplification.
Solving the low efficiency and the drug resistance of small molecule kinase inhibitor antitumor drug is not only a hot point in the study but also a task of top priority. Currently, the researchers and scientists are exploring the effective solutions, in which the most promising solutions mainly include: (1) a multiple-kinase inhibitor that simultaneously targets multiple kinases relevant to the occurrence and development of tumor; (2) directly targeting the kinase that has developed the drug-resistant mutation. For example, EGFR is over expressed or abnormally and excessively activated in several tumor tissues of human. If a certain small molecule kinase inhibitor not only can inhibit the activity of EGFR, but also can inhibit the new-vessels or the activity of the oncogene or oncoprotein of the other key kinases regulating the cell growth and proliferation, e.g. kinases such as c-Kit, c-SRC, MET, BTK, ALK, Abl and FLT3, it can improve the efficiency of tumor treatment and reduce the occurrence rate of the drug resistance. For example, as stated hereinbefore, after EGFR inhibitors Gefitinib and Erlotinib are used, EGFR itself is prone to experience a second mutation based on the original mutation (i.e., EGFR sensitive mutation), i.e., T790M mutation in EGFR. The occurrence of this second mutation is one of the main reasons causing EGFR inhibitors Gefitinib and Erlotinib to be ineffective. Therefore, the research and development of an EGFR kinase inhibitor that directly targets the drug resistant mutation (i.e. T790M mutation) is a direct approach of overcoming the drug resistance of this tumor.